June 1, 2013

Received 11 March 2013; received in revised form 15 May 2013; accepted 15 May 2013. published online 28 May 2013. Accepted Manuscript

Abstract

Background

There is a need for interferon-free treatment regimens for hepatitis C virus (HCV) infection. The goal of this study was to evaluate ABT-450, a potent HCV NS3 protease inhibitor, combined with low-dose ritonavir (ABT-450/r), in addition to ABT-333, a nonnucleoside NS5B polymerase inhibitor, and ribavirin, for the treatment of HCV infection.

Methods

We conducted a 12-week, phase 2a, open-label study involving patients who had HCV genotype 1 infection without cirrhosis. All patients received ABT-333 (400 mg twice daily) and ribavirin (1000 to 1200 mg per day) and one of two daily doses of ABT-450/r. Groups 1 and 2 included previously untreated patients; group 1 received 250 mg of ABT-450 and 100 mg of ritonavir, and group 2 received 150 mg and 100 mg, respectively. Group 3, which included patients who had had a null or partial response to previous therapy with peginterferon and ribavirin, received daily doses of 150 mg of ABT-450 and 100 mg of ritonavir. The primary end point was an undetectable level of HCV RNA from week 4 through week 12 (extended rapid virologic response)

Results

A total of 17 of the 19 patients in group 1 (89%) and 11 of the 14 in group 2 (79%) had an extended rapid virologic response; a sustained virologic response 12 weeks after the end of treatment was achieved in 95% and 93% of the patients, respectively. In group 3, 10 of 17 patients (59%) had an extended rapid virologic response, and 8 (47%) had a sustained virologic response 12 weeks after therapy; 6 patients had virologic breakthrough, and 3 had a relapse. Adverse events included abnormalities in liver-function tests, fatigue, nausea, headache, dizziness, insomnia, pruritus, rash, and vomiting

Conclusions

This preliminary study suggests that 12 weeks of therapy with a combination of a protease inhibitor, a non-nucleoside polymerase inhibitor, and ribavirin may be effective for treatment of HCV genotype 1 infection. (Funded by Abbott; ClinicalTrials.gov number, NCT01306617.).

For those awaiting changes in the treatment of hepatitis C, it's almost time to toss the confetti. The field is on the verge of one of the most profound upgrades in any therapeutic category, promising real progress in efficacy, tolerability and convenience. Barring any safety bombshells, a prolific pipeline of direct-acting anti-viral agents (DAAs) is due to start issuing forth options that, when combined, will permit all-oral, interferon-free treatment.

By making future HCV treatment shorter, safer, easier and more effective, says Jonathan Fenkel, MD, director of the hep. C center at Thomas Jefferson University, these protocols “will open the door to many more patients who have declined or deferred treatment.”

That could mean billions in sales. Analysts say new therapies could help grow the pie for the virus to $20 billion annually by 2020. The infectious diseases market, as a whole, rose from $33.6 billion in 2011, to $35.2 billion in 2012, according to data compiled by IMS Health on sales of hep. C and HIV drugs, as well as antibiotics and vaccines.

Clinicians and analysts agree that the first and likely go-to therapy will eventually be Gilead Sciences' sofosbuvir (GS-7977). Gilead has applied for approval of sofosbuvir and ribavirin as an all-oral therapy for patients with genotypes 2 and 3—the minority of patients with hep. C in the US (about 75% of patients are genotype 1).

Gilead's agent is the “holy grail of HCV treatment,” analyst Julie Hoggatt tells MM&M. The first hep. C drug to cut treatment duration to 12 weeks, vs. 24 weeks with the available DAAs (Vertex's Incivek or Merck's Victrelis), it boosts efficacy from a 70% cure rate to over 80%. Phase II data from Gilead suggest a further 33% reduction in treatment duration—from 12 weeks down to eight—in patients taking a combination of sofosbuvir and Gilead's ledipasvir, aka GS-5885.

The nucleotide analogue polymerase inhibitor (or “nuc”) has broad-spectrum genomic activity (meaning that it covers multiple hep. C genotypes), a barrier to the development of viral resistance, has once-daily dosing, and can be co-formulated with other agents.

Other players include AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Merck, Vertex and smaller biotechs. Some could find a niche among the difficult-to-treat population. But, says Hoggatt, a principal with Symphony Health Solutions' inThought Research, “We are forecasting Gilead to be the clear majority player, with sofosbuvir capturing 75% peak market share.” She predicts approval as early as mid-December for use in genotypes 2 and 3. By 2015, sofosbuvir's label is likely to be expanded as part of an all-oral regimen for the more common genotype 1, when combined with ledipasvir.

In the meantime, inThought expects some off-label use of sofosbuvir plus ribavirin without interferon in treatment-naïve genotype 1 patients, the analyst wrote in an April research note in which she modeled peak worldwide sales of $4.3 billion for sofosbuvir. This is a conservative forecast, below street consensus which is over $7 billion.

“Shortening treatment and lowering the pill burden will have a huge effect on compliance, efficacy, and acceptance,” says Jefferson's Fenkel. Not to mention safety: IMS analyst Steve Gubernick notes, “You don't have to worry about paying for side effects anymore.”

This is a wholesale transformation from today's standard of care, which incorporates pegylated interferon (PEG-IFN), ribavirin and a protease inhibitor (Incivek or Victrelis). Many of today's HCV treaters are holding patients back until the new wave of oral medication hits.

According to Hoggatt and others, the next most-dominant company in the HCV market after Gilead will likely be AbbVie, whose multi-drug oral regimen has high efficacy among null responders. It scored FDA's “breakthrough” status, as did BMS hep. C drug daclatasvir.

In testing, daclatasvir with asunaprevir and BMS-791325, produced a high cure rate in prior treatment failures. And BI presented data on NS3/4a protease inhibitor faldaprevir which, in conjunction with pegylated interferon and RBV, had a 79-80% rate of cure in a group that had a high proportion of tough-to-treat cirrhotic patients.

Hep. C is, for most patients, not fast-moving, so they can wait for new options. In a research note, ISI Group analyst Mark Schoenebaum, MD, estimated that around 350,000 US patients are under the care of a hep. C specialist and can be easily accessed and activated once new treatments arrive. The challenge is getting patients diagnosed and into the medical system; and, once they are, managing the potential flood of treatment-eligible patients. There are about three million infected patients in the US, four million in Western Europe, about a million in Japan and seven million in Eastern Europe.

Another caveat: Who'll pay for the new regimens, which could cost $100,000 or more for a three-month course. While today's regimens cost from $65,000-$80,000, according to ISI's Schoenebaum, “I [w]ould be very surprised if [sofosbuvir] were priced significantly less than $80k, and wouldn't be shocked to see $100k.” inThought's Hoggatt models a wholesale cost closer to $54,000 for a 12-week course.

What is dictated by the payers will be important. “If we have equal efficacy and side-effect profiles for all of the regimens, the payers may have preferences,” says Paul Pockros, MD, division head of gastroenterology and hepatology at the Scripps Clinic in San Diego. Of course, all of this new drug excitement is unfolding against the backdrop of ObamaCare, rolling out in 2014. That means more people covered, but leaves guesswork as to the span of pharmaceutical coverage.

While a revolution is under way in hep. C, in HIV/AIDS it's more of an evolution. With the approval of Gilead's quad-pill Stribild, there are three one-pill, once-a-day, single-tablet regimens available, all with high efficacy and favorable tolerability. Attention is focused mostly on the safest, most convenient way to treat patients chronically for life.

“Our focus is still on the safest regimens that give patients a healthy lifespan without cumulative toxicities,” says Cal Cohen, MD, a leader in HIV research and an instructor at Harvard University. Cohen spotlights two investigational anti-retroviral medications in the pipeline. Gilead's tenofovir alafenamide fumarate (TAF; GS-7340) has so far shown greater antiviral activity with potentially fewer concerns about kidney function or bone mineral density. The other investigational agent Cohen's eying is ViiV's second-generation integrase inhibitor dolutegravir, which has demonstrated sustained efficacy and once-daily dosing, without the need for a pharmacokinetic booster.

CLINICAL CORNER

The days of interferon are numbered. So, what are the next important milestones in the evolution of hepatitis C drug development? The two next big signposts, sources say, are the removal of ribavirin from treatment protocols as well as the further truncating of HCV regimens to as short as eight weeks, down from today's 24-48.

Ribavirin is a double-edged sword. It has been shown to reduce the rate of relapse and it's cheap. But it's a weak anti-viral whose mechanism of action against HCV is not well understood, and it's dosed twice daily. RBV, as it's known, also brings such side effects as anemia, so physicians can't dose it in patients with kidney impairment, and teratogenicity (a contraindication in pregnant women).

The latter “complicates recruiting women of child-bearing age into clinical trials—a substantial number of HCV patients!” says Wayne Dankner, MD, global therapeutic area lead for infectious diseases and pediatrics with the CRO Parexel. It also affects male subjects as they must “practice adequate birth control with their female partners,” he adds.

Multiple strains of evidence from the clinical literature suggest that it may be possible to show ribavirin the door. Manufacturers like Gilead, AbbVie and Bristol-Myers Squibb are trying to identify other direct-acting anti-virals that can replace RBV in the regimen or to find agents that are sufficiently robust to obviate the need for it altogether.

The other opportunity on the horizon is to reduce the duration of therapy—an opportunity highlighted by the announcement of Gilead's Phase II Lonestar data in early May. Lonestar demonstrated a 95-100% cure rate after eight weeks of therapy with a fixed dose combination of Gilead's nuc sofosbuvir plus the NS5a ledipasvir (GS-5885).

“While most of these regimens are 12 weeks in duration, there is a continual focus on whether we can shorten to eight weeks. That would improve acceptance and lessen exposure to drugs,” says Dankner.

Another important future development is providing effective therapy to patients with more advanced liver disease, such as cirrhosis, and those with multiple co-morbidities, including HCV/HIV co-infection. Such patients have historically been much more difficult to treat.

“Enrollment of a population representative of the disease being treated is critically important,” says Peter Piliero, MD, Boehringer Ingelheim VP, clinical development and medical affairs. Other typical patient characteristics, Piliero adds, include those with both HCV genotype 1 subtypes (1a and 1b) and the various IL28b polymorphisms.

But scientists looking for new HCV treatments are not starting from scratch. Most of the companies in the field have cut their teeth developing antiretroviral agents for HIV. “We'll have a second generation of agents coming right on the heels of the first generation,” says UCSD School of Medicine's Bob Gish, MD, chief of clinical hepatology and professor of clinical medicine. “The warp speed we're seeing is because of that historical experience in other viral illnesses.”

GileadSciences (GILD) announced on May 21, 2013 that the European regulator EMA (European Medicines Agency) started the process of assessing the company's once daily oral treatment for hepatitis C virus (HCV) and will furnish an accelerated review.

Earlier, on May 13, Johnson&Johnson's (JNJ) experimental drug, still in mid-stage trial, got priority review status from the FDA. A week earlier, the FDA accorded breakthrough status to the Hepatitis C virus regimen of AbbVie (ABBV).

The race, therefore, is on.

The disease

Hepatitis C is caused by infection of the hepatitis C virus that attacks the liver causing inflammation and long term complications. 40% of the patients infected with HCV recover fully and the remaining 60% become chronic carriers, regardless of whether they have symptoms or not. 20% of these develop cirrhosis. 20% of patients suffering from cirrhosis develop liver cancer. Europe alone has roughly four million carriers and 3% of the world's population has HCV. That is roughly 80% of the U.S. population, in number terms.

Currently, standard treatment for HCV is a 24-28 week therapy with ribavirin (a nucleoside inhibitor) and peg-IFN (pegylated interferon) injections, which cause significant side effects such as flu-like symptoms that persist through the course of the treatment. Protease inhibitors, Victrelis from Merck & Co (MRK) and Incivek, developed by Vertex Pharmaceuticals (VRTX) in partnership with Johnson & Johnson, helped improve cure rates but still involved side effects as these treatments also involved interferon injections.

The market for HCV is expected to grow to $8.5 billion by the end of 2016. A Bloomberg report estimates the market for new HCV drugs to reach $20 billion by 2020.

Gilead's sofosbuvir

Sofosbuvir was discovered by Pharmasset, a New Jersey company that Gilead acquired in November 2011 for $11 billion. Gilead submitted sofosbuvir for approval in early April. The FDA normally takes two months before accepting a new drug application (NDA) for a 10-month review. A priority review takes 6 months. Gilead's MAA (Marketing Authorization Application) before EMA was submitted on April 17, 2013 and validation by EMA is indeed good news for Gilead's investors.

With the stated goal of increasing injection safety, the CDC unveiled a new set of guidelines powered by a catchy phrase -- "the four Es" and then worked to tailor a set of clunky descriptions phrase.

The "Es" in question are:

Epidemiologic surveillance of unsafe injection

Education

Enforcement of safe practices

Engineering devices to reduce risks

Among safe injection practices that help prevent the spread of disease, healthcare professionals should never administer medications from the same syringe or single-dose vial to multiple patients, nor should they enter a vial with a used syringe or needle, wrote Joseph Perz, DrPH, of the CDC, and co-authors online in Morbidity and Mortality Weekly Report.

"The U.S. experience with outbreaks attributed to unsafe injection practices has grown substantially over recent years," the authors said, noting at least 49 outbreaks since 2001 attributable to "extrinsic contamination of injectable medical products at the point of administration," the majority of which involved hepatitis B or C, but also included bacterial and invasive bloodstream infections.

The guidelines classified unsafe injection practices into two categories: reuse of syringes and mishandling of injectable drugs.

Syringe reuse was further broken down into direct and indirect reuse. Direct reuse involves injecting multiple patients with a single syringe, while indirect reuse involves using multiple syringes through a shared medication vial.

The authors identified mishandling of medication as using single-dose vials and intravenous solution bags to treat multiple patients.

The authors concluded with a caution that unsafe injection practices are not limited to any one procedure or setting, and that unsafe injection practices increase fiscal and emotional burdens, as well as disease burdens, for patients, practitioners, and public health and medical care systems. Despite these risks, they noted, the problem is entirely preventable.

Hep C may be thwarted by muting its ability to replicate. Also this week: a promising approach to preserve muscle in ALS, and the body's microbiota fight a sexually-transmitted disease.

Stopping HCV in Its Tracks

Researchers have identified a possible new approach to stopping hepatitis C virus (HCV) infection that involves attacking the virus's ability to reproduce.

The attack was brought by agents called RNA aptamers, which work by binding to and disabling the NS5B replicase enzyme involved in replication of the virus.

As Seong-Wook Lee, PhD, of Dankook University in South Korea, and colleagues reported in the Journal of Virology, the agents inhibited replication of two variants of HCV -- genotypes 1b and 2a -- in cultured human liver cells without inducing toxicity or innate immunity. Also, there were no signs that the approach induced resistance.

The aptamers were then modified for in vivo availability and liver-specific delivery. When administered intravenously to mice, the aptamers entered liver tissue at concentrations that suggested therapeutically effective quantities could be achieved in human patients.

-- Todd Neale

Growth Factors Preserve Muscle in ALS

Implanting human stem cells into the leg muscles of a rat model of amyotrophic lateral sclerosis (ALS) led to delay in disease onset, preservation of muscle function, and longer survival, researchers from the University of Wisconsin reported.

Masatoshi Suzuki, PhD, and colleagues performed a series of experiments in which stem cells that release specific growth factors were injected into the neuromuscular junction, where the neurons attach to the muscles in the leg.

These growth factors, glial cell line-derived neurotropic factor and vascular endothelial growth factor, together had synergistic effects in preserving motor function and survival in the animals, the researchers reported in Molecular Therapy.

These stem cells and growth factors are already being used in other clinical contexts, and a clinical trial of stem cell transplantation into the spines of ALS patients is ongoing. But implanting the cells into muscles of the legs and even the diaphragm would be a simpler process if similar improvements can be demonstrated in humans, the researchers noted.

-- Nancy Walsh

Lactic Acid Bacterium Fights Trichomonas

Women have a natural bacterium that fights a sexually transmitted infection, stated researchers from the University of Auckland in New Zealand.

The parasite Trichomonas vaginalis binds to the vaginal wall and damages cells lying there. But they first must overcome "an unfavorable environment dominated by lactobacilli," which is a lactic acid bacterium, according to the study published online in the journal Sexually Transmitted Infections.

"Understanding the role that Lactobacillus plays in T vaginalis infection/disease might reveal new therapeutic approaches which include taking advantage of the natural probiotic activity of lactobacilli," the authors said.

-- Kathleen Struck

Body Clock Key to Immune Response

It may be the time of day that determines one's resistance to bacterial infections.

Up to 15% of human genes are regulated by the day-night pattern of circadian rhythms. With this in mind, Paolo Sassone-Corsi, PhD, from UC Irvine, and colleagues found that the ability of mice to fend off infection was linked to circadian-controlled genes.

Understanding the circadian genetics regulating immunity "gives us the ability to target treatments that supplement the power of the body clock to boost immune response," Sassone-Corsi said in a statement.

The study was published online in the Proceedings of the National Academy of Sciences.

Long have researchers been tantalized by the promise of generating artificial liver tissue for transplantation.

Unlike other organs, the liver can regenerate itself when part is removed -- but only within the body. Once taken from the body, mature liver cells known as hepatocytes quickly lose their ability to function. "It's a paradox because we know liver cells are capable of growing, but somehow we can't get them to grow" outside the body, Sangeeta Bhatia, an engineer at MIT, told reporters.

Bhatia, a professor of health sciences and technology and electrical engineering and computer science, is a senior associate member of the Broad Institute, which focuses on the molecular underpinnings of disease, as well as a member of the university's Koch Institute for Integrative Cancer Research, and Institute for Medical Engineering and Science. On Sunday, Bhatia and her colleagues published a paper in Nature Chemical Biology, reporting the identification of a dozen chemical compounds that help liver cells not only maintain normal function while grown in the laboratory but also to produce new tissue.

Such a breakthrough may help researchers develp engineered tissue to treat people suffering from chronic liver diseases such as hepatitis C -- approximately one of every 14 people on the planet.

A relatively complex organ, the liver serves some 500 functions, divided into four general categories, including drug detoxification, energy metabolism, protein synthesis, and bil production. David Thomas, an associate researcher at the Broad Institute, measured expression levels of 83 liver enyzmes representing some of the trickiest functions for the liver to maintain. After screening thousands of hepatocytes from eight different tissue donors, the investigators identified a dozen compounds that help the cells maintain those functions, helped to regenerate cells, or both. They managed to adapt the system so that liver cells grew, in layers with the fibroblast cells, in small depressions in a lab dish, allowing researchers to rapidly study how 12,500 different chemicals affect hepatocyte function and regeneration.

When two of the compounds appeared to work especially well in cells from younger donors, investigators then tested them in liver cells generated from induced pluripotent stem cells. Though previous attempts with such stem cells had failed to generate mature liver cells, the compounds got the job done. Bhatia and her colleagues now wonder whether the compounds might work to help mature other types of cells, too. As other scientists investigate that question, the MIT team plans next to embed the treated liver cells on scaffolds of polymer tissue for implantation into mice, to test whether they might be suitable for liver tissue transplants. They also plan to investigate whether they can use the compounds to develop drugs that would help regenerate liver tissue within the body, without a trasplant operation.

The MIT researchers collaborated with scientists at Harvard University and the University of Wisconsin on the project, which received funding from the National Institutes of Health.

Will the new crop of hepatitis C treatments form the next battleground between the pharmaceutical industry, poor nations and patient advocates? A new report from the Global Commission on Drug Policy, which includes former Federal Reserve Chairman Paul Volcker and billionaire businessman Richard Branson, suggests compulsory licenses should be pursued when pricing talks with drugmakers fail.

“Governments should enhance their efforts to reduce the costs of new and existing hepatitis C medicines – including through negotiations with pharmaceutical companies to ensure greater treatment access for all those in need. Governments, international bodies and civil society organizations should seek to replicate the successful reduction in HIV treatment costs around the world, including the use of patent law flexibilities to make them more accessible,” the report recommends (here is the report).

The mention of ‘patent law flexibilities’ refers to a World Trade Organization pact called TRIPS, or Agreement on Trade-Related Aspects of Intellectual Property Rights, which allows countries to pursue compulsory licensing as an option to make patented medicines more affordable to their citizens. But this has been a contentious provision for the pharmaceutical industry.

Brand-name drugmakers argue that overriding patents with compulsory licenses robs them of incentives and rewards for investing in innovative research, while patient advocates say licensing is the only means to make high-priced medicines affordable. The issue has caused several high-profile disputes in recent years in such countries as Thailand, Brazil and South Africa involving various HIV and cancer treatments.

Last year, India entered the fray when a license was authorized for a Bayer cancer medicine. The drugmaker appealed, but the license was upheld two months ago. The episode has been described as a game changer, because the move is expected to encourage still other Indian generic drugmakers to seek licenses for all sorts of medicines in one of the world’s largest and fastest-growing markets, although Indian authorities have been debating the issue (read more here and here).

Hepatitis C, however, is quickly landing on radar screens in developing and poor nations. About 170 million people are infected globally, including 10 million who inject drugs, but the commission found that drug enforcement laws in many countries are forcing drug users away from public health services into riskier settings where the virus abounds. And this is increasing pressure for medicinal solutions.

But the commission report notes that “if treatment access remains low, there will be a rising number of people who use drugs who develop advanced or fatal liver disease” and the use of hepatitis C drugs “will be severely limited if they are not affordable for low and middle income countries… Reducing the costs of existing and future hepatitis treatments should be an urgent priority for all national and international authorities.”

“If the prices were to be unaffordable once more in history, it would be one more scandal around inequity of access to health care,” Michel Kazatchkine, the United Nations Secretary General’s Special Envoy on HIV/AIDS in Eastern Europe and Central Asia, said at a briefing in Geneva yesterday where the report was disclosed, according to Bloomberg News. “There’s no reason why a country like Ukraine wouldn’t go for this and declare a public emergency.”

Several drug makers are unlikely to be pleased with the report, since the hepatitis C market has grown crowded due to the burgeoning need. Gilead Sciences, for instance, recently sought regulatory approval for a drug that was part of its $11 billion for Pharmasset in 2011 (see this). Mark Schoenebaum, an analyst at ISI Group, believes Gilead may charge as much as $100,000 per patient, at least in the US, and Leerink Swann analyst Howard Liang estimates the drug could become a $9 billion seller by 2015. Others playing in this market include Merck, Johnson & Johnson and Vertex Pharmaceuticals.

Although PhRMA has derided compulsory licensing (read this), the industry trade group has not issued a response to the report.

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